{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:09:38Z","timestamp":1780596578338,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Fever of unknown origin (FUO) remains a persistent diagnostic challenge in clinical medicine despite significant advances in laboratory testing and imaging techniques. The definition of FUO has evolved since the original criteria proposed in 1961 and currently refers to persistent fever exceeding approximately 38.2\u201338.3 \u00b0C without a definitive diagnosis after an adequate diagnostic evaluation. Gastrointestinal diseases represent an important but often underrecognized group of conditions associated with FUO. The aim of this review is to synthesize current evidence on the gastroenterological causes of FUO, with particular emphasis on pathophysiological mechanisms, diagnostic strategies, and therapeutic management. The analysis highlights the role of inflammatory, infectious, and neoplastic gastrointestinal disorders in the etiology of prolonged fever. Key mechanisms involve systemic inflammatory responses mediated by cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor, as well as immune processes associated with the gut-associated lymphoid tissue (GALT) and interactions between intestinal microbiota and host immunity. Among the most frequently reported gastroenterological causes of FUO are inflammatory bowel diseases, intra-abdominal infections and abscesses, hepatobiliary disorders, pancreatitis, and gastrointestinal malignancies. Diagnostic evaluation requires a stepwise approach integrating laboratory testing, microbiological studies, imaging modalities, and endoscopic procedures, with advanced techniques such as computed tomography and fluorodeoxyglucose positron emission tomography improving detection of occult inflammatory or neoplastic processes. Therapeutic management is primarily guided by the identification of the underlying cause, while empirical treatment should be carefully considered to avoid masking diagnostic clues. A better understanding of the gastrointestinal mechanisms underlying FUO and the development of more efficient diagnostic algorithms may improve clinical outcomes and reduce the number of undiagnosed cases.<\/jats:p>","DOI":"10.3390\/jcm15114350","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:11:04Z","timestamp":1780593064000},"page":"4350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Possible Gastroenterological Causes of FUO (Fever of Unknown Origin)"],"prefix":"10.3390","volume":"15","author":[{"given":"Oliwia","family":"Cichy","sequence":"first","affiliation":[{"name":"Student Scientific Association, Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9461-9204","authenticated-orcid":false,"given":"Aleksandra","family":"Wojno","sequence":"additional","affiliation":[{"name":"Student Scientific Association, Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8008-3706","authenticated-orcid":false,"given":"Agata","family":"Wojno","sequence":"additional","affiliation":[{"name":"Student Scientific Association, Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3157-204X","authenticated-orcid":false,"given":"Anna","family":"Karwowska","sequence":"additional","affiliation":[{"name":"Student Scientific Association, Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olgierd","family":"Dr\u00f3\u017cd\u017c","sequence":"additional","affiliation":[{"name":"Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Rabczy\u0144ski","sequence":"additional","affiliation":[{"name":"Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3624-3691","authenticated-orcid":false,"given":"Katarzyna","family":"Madziarska","sequence":"additional","affiliation":[{"name":"Clinical Department of Diabetology, Hypertension and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00005792-196102000-00001","article-title":"Fever of Unexplained Origin: Report on 100 Cases","volume":"40","author":"Petersdorf","year":"1961","journal-title":"Medicine"},{"key":"ref_2","unstructured":"(2026, March 12). Fever of Unknown Origin\u2014Reexamined and Redefined\u2014PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/1651090\/."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nguyen, T.K., Nguyen, Y.H., Nguyen, H.T., Khong, Q.M., and Tran, N.K. (2022). Etiologies of Fever of Unknown Origin in HIV\/AIDS Patients, Hanoi, Vietnam. BMC Infect. Dis., 22.","DOI":"10.1186\/s12879-022-07049-3"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"280","DOI":"10.7861\/clinmedicine.15-3-280","article-title":"Fever of Unknown Origin","volume":"15","author":"Simon","year":"2015","journal-title":"Clin. Med."},{"key":"ref_5","first-page":"e32472","article-title":"Fever of Unknown Origin and Atrial Fibrillation: A Case Report","volume":"14","author":"Knopp","year":"2022","journal-title":"Cureus"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wu, Z.-G., Song, Z.-Y., Wang, W.-X., Xi, W.-N., Jin, D., Ai, M.-X., Wu, Y.-C., Lan, Y., Song, S.-F., and Zhang, G.-C. (2022). Human Brucellosis and Fever of Unknown Origin. BMC Infect. Dis., 22.","DOI":"10.1186\/s12879-022-07872-8"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106443","DOI":"10.1016\/j.ejim.2025.106443","article-title":"Fever and Inflammation of Unknown Origin in the 21st Century","volume":"142","author":"Antoniadou","year":"2025","journal-title":"Eur. J. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.cmi.2023.08.010","article-title":"Update on Imaging in Fever and Inflammation of Unknown Origin: Focus on Infectious Disorders","volume":"30","author":"Betrains","year":"2024","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.2147\/CLEP.S386328","article-title":"Fever of Unknown Origin: A Validation Study of Danish ICD-10 Diagnosis Codes","volume":"14","author":"Gedebjerg","year":"2022","journal-title":"Clin. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1515\/dx-2024-0200","article-title":"A Scoping Review of Fever of Unknown Origin with Normal Serum C-Reactive Protein","volume":"12","author":"Kano","year":"2025","journal-title":"Diagnosis"},{"key":"ref_11","first-page":"137","article-title":"Fever of Unknown Origin in Adults","volume":"105","author":"David","year":"2022","journal-title":"Am. Fam. Physician"},{"key":"ref_12","first-page":"299","article-title":"Distribution of the Causes of Fever of Unknown Origin in China, 2013\u20132022","volume":"12","author":"Kang","year":"2024","journal-title":"J. Transl. Int. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1080\/21548331.2020.1775453","article-title":"Fever of Unknown Origin: Evaluation of 110 Classical and HIV-Associated Cases in the Last Decade","volume":"50","author":"Karabela","year":"2022","journal-title":"Hosp. Pract. (1995)"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.3855\/jidc.17610","article-title":"Clinical Features of Patients Presenting with Fever of Unknown Origin Caused by Non-Tuberculous Mycobacterium Infection","volume":"17","author":"Liu","year":"2023","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Trapani, S., Fiordelisi, A., Stinco, M., and Resti, M. (2023). Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach. Children, 11.","DOI":"10.3390\/children11010020"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e049840","DOI":"10.1136\/bmjopen-2021-049840","article-title":"Fever of Unknown Origin (FUO) in Children: A Single-Centre Experience from Beijing, China","volume":"12","author":"Hu","year":"2022","journal-title":"BMJ Open"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e080847","DOI":"10.1136\/bmj-2024-080847","article-title":"Fever of Unknown Origin","volume":"388","author":"Wright","year":"2025","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"880","DOI":"10.3855\/jidc.18192","article-title":"Fever of Unknown Origin: A 12-Year Case Series in Colombia","volume":"18","author":"Mackenzie","year":"2024","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tong, X., Zhan, T., Dong, X., and Xu, D. (2024). Fever of Unknown Origin Associated with Immune Checkpoint Inhibitors. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1364128"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1186\/s13023-022-02444-0","article-title":"Chromosomal Abnormalities Related to Fever of Unknown Origin in a Chinese Pediatric Cohort and Literature Review","volume":"17","author":"Sun","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/INF.0000000000003686","article-title":"Fever of Unknown Origin in a 6-Year-Old","volume":"42","author":"Nigam","year":"2023","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2214\/AJR.22.28726","article-title":"FDG PET in Evaluation of Patients With Fever of Unknown Origin: AJR Expert Panel Narrative Review","volume":"221","author":"Palestro","year":"2023","journal-title":"Am. J. Roentgenol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Candelli, M., Franza, L., Pignataro, G., Ojetti, V., Covino, M., Piccioni, A., Gasbarrini, A., and Franceschi, F. (2021). Interaction between Lipopolysaccharide and Gut Microbiota in Inflammatory Bowel Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126242"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.it.2024.01.006","article-title":"Gut-Associated Lymphoid Tissue: A Microbiota-Driven Hub of B Cell Immunity","volume":"45","author":"Bemark","year":"2024","journal-title":"Trends Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/s41430-021-00877-7","article-title":"The Effect of Enteral Stimulation on the Immune Response of the Intestinal Mucosa and Its Application in Nutritional Support","volume":"75","year":"2021","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kunst, C., Schmid, S., Michalski, M., T\u00fcmen, D., Buttensch\u00f6n, J., M\u00fcller, M., and G\u00fclow, K. (2023). The Influence of Gut Microbiota on Oxidative Stress and the Immune System. Biomedicines, 11.","DOI":"10.3390\/biomedicines11051388"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e117131247647","DOI":"10.33448\/rsd-v13i12.47647","article-title":"Imunidade Intestinal Mediada Pelo GALT (Tecido Linfoide Associado Ao Intestino) Nas Doen\u00e7as Inflamat\u00f3rias Intestinais","volume":"13","author":"Bertoldi","year":"2024","journal-title":"Res. Soc. Dev."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yoo, J.Y., Groer, M., Dutra, S.V.O., Sarkar, A., and McSkimming, D.I. (2020). Gut Microbiota and Immune System Interactions. Microorganisms, 8.","DOI":"10.3390\/microorganisms8101587"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2023013","DOI":"10.4084\/MJHID.2023.013","article-title":"Fever of Unknown Origin and Multidrug Resistant Organism Colonization in AML Patients","volume":"15","author":"Guarnera","year":"2023","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2215000","DOI":"10.1001\/jamanetworkopen.2022.15000","article-title":"Prospective Studies Comparing Structured vs Nonstructured Diagnostic Protocol Evaluations Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-Analysis","volume":"5","author":"Wright","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30502225251321030","DOI":"10.1177\/30502225251321030","article-title":"Fever of Unknown Origin in Children: A 14-Year, Single Institution Retrospective Review","volume":"12","author":"Lim","year":"2025","journal-title":"Sage Open Pediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.mcna.2023.05.016","article-title":"Fever of Unknown Origin","volume":"108","author":"Ryan","year":"2024","journal-title":"Med. Clin. N. Am."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/cid\/ciac040","article-title":"Fever of Unknown Origin and Incidence of Cancer","volume":"75","author":"Sogaard","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Fusco, F.M., Pisapia, R., Nardiello, S., Cicala, S.D., Gaeta, G.B., and Brancaccio, G. (2019). Fever of Unknown Origin (FUO): Which Are the Factors Influencing the Final Diagnosis? A 2005\u20132015 Systematic Review. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4285-8"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"ofae298","DOI":"10.1093\/ofid\/ofae298","article-title":"Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel","volume":"11","author":"Wright","year":"2024","journal-title":"Open Forum Infect. Dis."},{"key":"ref_36","unstructured":"(2026, March 12). Fever of Unknown Origin\u2014StatPearls\u2014NCBI Bookshelf, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK532265\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s11604-022-01306-w","article-title":"Optimal Use of the FDG-PET\/CT in the Diagnostic Process of Fever of Unknown Origin (FUO): A Comprehensive Review","volume":"40","author":"Minamimoto","year":"2022","journal-title":"Jpn. J. Radiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E36628","DOI":"10.1097\/MD.0000000000036628","article-title":"Multidisciplinary Approach to Diagnosis and Management of Fever of Unknown Origin: A Case Report","volume":"102","author":"Chen","year":"2023","journal-title":"Medicine"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kaya, M.S., Kaya, S.Y., Karaali, R., Can, G., Balkan, \u0130.\u0130., Mete, B., Tabak, F., and Salto\u011flu, N. (2025). Fever of Unknown Origin (FUO): A 7-Year Clinical Experience, Etiological Distribution, and Diagnostic Approaches. BMC Infect. Dis., 25.","DOI":"10.1186\/s12879-025-11979-z"},{"key":"ref_40","first-page":"e96341","article-title":"Rare Presentation of Fever of Unknown Origin: A Diagnostic Challenge","volume":"17","author":"Kondolay","year":"2025","journal-title":"Cureus"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chiappini, E., Orlandi, M., Chiarugi, A., Di Mauro, A., Insalaco, A., Milani, G.P., Vallini, M., and Lo Vecchio, A. (2024). Fever Management in Children and Insights into Fever of Unknown Origin: A Survey among Italian Pediatricians. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1452226"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/11\/4350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:27:54Z","timestamp":1780594074000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/11\/4350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcm15114350"],"URL":"https:\/\/doi.org\/10.3390\/jcm15114350","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}